References to excessive and unexplained bleeding have been made since antiquity. In the Talmud, a collection of Jewish Rabbinical writings from the 2nd century AD, it was written that male babies did not have to be circumcised if two brothers had already died from the procedure. In the 12th century AD, an Arabian physician from Cordoba named Albucasis wrote of males in a particular village, who had died of uncontrollable bleeding. Occasional references to bleeding can be found in the scientific literature of following centuries.
In the U.S., the transmission of hemophilia from mothers to sons was first described in the early 19th century. In 1803, the Philadelphia physician Dr. John Conrad Otto wrote an account of "a hemorrhagic disposition existing in certain families." He recognized that a particular bleeding condition was hereditary and predominately affected males. He traced the disease back through three generations to a woman who had settled near Plymouth, New Hampshire in 1720. The word "hemophilia" first appeared in a description of a bleeding disorder condition at the University of Zurich in 1828.
A Royal Disease
Hemophilia has often been called the "Royal Disease." Queen Victoria of England (1837-1901) was a carrier of the hemophilia gene and subsequently passed the disease on to several royal families. Victoria’s eighth child Leopold had hemophilia and suffered from frequent hemorrhages, which were reported in the British Medical Journal in 1868. Leopold died at the age of 31 of a brain hemorrhage. Leopold’s daughter Alice was a carrier, and her son, Viscount Trematon was born with hemophilia. Viscount died in 1928, of a brain hemorrhage similar to the one that killed his grandfather.
Nicholas and Alexandra
Hemophilia played an important role in the Russian Royal family. Two of Queen Victoria's daughters, Alice and Beatrice, were carriers of hemophilia. They passed the disease on to the Spanish, German and Russian royal families, ensuring that the disease would be present in future generations. Alexandra, Queen Victoria's granddaughter, married Nicholas, the Tsar of Russia in the early 20th century. Alexandra was a carrier of the disease and her first son Alexei, was born with hemophilia. Nicholas and Alexandra were pre-occupied by the health problems of their son at a time when Russia was in turmoil. The monk Rasputin gained great influence in the Russian court, partly because he was the only one able to help the young Tsarevich Alexei. He used hypnosis to relieve Alexei's pain. The use of hypnosis not only relieved pain, but may have also helped slow or stop the boy's hemorrhages. The illness of the heir to the Tsar's throne, the strain it placed on the Royal family, and the power wielded by the mad monk Rasputin were all factors leading to the Russian Revolution of 1917. In 1916, the 45-year old faith-healer Rasputin was assassinated in Petrograd by group of noblemen bent on ridding Russia of the monk's corrupting influence on Nicholas II and Alexandra.
Finding the Cause
In the 20th century doctors looked for the cause of excessive bleeding. Until then, they had believed that the blood vessels of people with hemophilia were simply more fragile.
von Willebrand disease, the most common hereditary bleeding disorder, was first recognized by the Finnish physician Erik von Willebrand in 1925. He published his first paper on the disease in 1926. In it, he presented the pedigree of a Scandinavian family from the island of Aland, reporting bleeding symptoms in 23 of 66 family members.
Doctors previously thought defective platelets were the likely cause of bleeding disorders. But in 1937, doctors at Harvard University found they could correct the clotting problem by adding platelet-free plasma. They called the substance "anti-hemophilic globulin."
In 1944 Dr. Pavlosky from Buenos Aires, Argentina, did a lab test which showed that blood from a person with hemophilia could correct the clotting problem in a second person with hemophilia and vice-versa. He had stumbled upon two patients, each with a deficiency in different proteins - Factor VIII and Factor IX. This led to the eventual recognition of hemophilia A and hemophilia B as two distinct diseases. By the end of the decade people with hemophilia had a life expectancy of less than 30 years. Treatment was limited to icing joints where internal bleeding occurred and painful transfusions of whole blood.
1950s & 1960s
In the 1950s and early 1960s, hemophilia and other bleeding problems were still being treated with whole blood or fresh plasma. Unfortunately, there were not enough factor VIII or IX proteins in these treatments to stop serious internal bleeding. Many people with severe hemophilia, and some people with mild or moderate forms, died in childhood or early adulthood. The most common causes of death were bleeding in vital organs, especially the brain, and excessive bleeding after minor surgery or trauma. Those who survived were often crippled by the long-term effects of repeated hemorrhages into the joints. The pressure of massive bleeding into joints and muscles made hemophilia one of the more painful diseases.
By the mid-1960s the clotting factors were identified and named. An article in Nature in 1964 described the clotting process in detail. The interaction of the different factors in blood clotting was termed the "coagulation cascade."
In 1965, Dr. Judith Graham Pool published a paper on cryoprecipitate. In a major breakthrough, Dr. Pool discovered that the precipitate left from thawing plasma was rich in factor VIII. She found that because cryoprecipitate contained a substantial amount of factor, it could be infused to control serious bleeding. Blood banks were able to produce and store the component, making emergency surgery and elective procedures for hemophilia patients more practicable. This advancement also ended the need for high-volume whole plasma transfusions for people with hemophilia.
By the 1970s, freeze-dried powdered concentrates containing factor VIII and IX became available. Factor concentrates revolutionized hemophilia care because they could be stored at home, making treatment easily accessible. People with hemophilia could now “self-infuse” factor products, drastically reducing the number of requisite hospital visits. Activities such as work and travel were now carried out with much greater ease, the benefits being increased convenience and independence.
Although hepatitis C was already present in the blood supply, by the early 1980s a new blood-borne disease would emerge. By the mid 1980s, it had become clear that HIV/AIDS could be transmitted though the use of blood and blood products, such as those used to treat hemophilia. Approximately half of the people with hemophilia in the U.S. would eventually become HIV-infected and thousands would die. The overwhelming impact of HIV on the hemophilia community would reverberate well into the next decade.
1990s to present
Treatment for hemophilia and other bleeding disorders advanced in the 1990s. The safety and efficacy of factor concentrates improved. Factor products became safer as tighter screening methods were implemented and advanced modes of viral inactivation were utilized. In addition, synthetic (not derived from plasma) factor products were manufactured using recombinant technologies. In 1992, the first recombinant factor VIII product was approved by the Food and Drug Administration (FDA). In 1997, the first factor IX product was granted FDA approval. Additional synthetic drugs such as desmopressin acetate (DDAVP) were also introduced to treat mild-to-moderate hemophilia A and von Willebrand disease.
By the mid 1990s prophylactic (a preventative treatment regimen) therapy in children with hemophilia became more common. Proponents argued that the implementation of prophylaxis would prevent the chronic bleeding episodes that typically characterized hemophilia. Since the advent of prophylaxis, children could look forward to a life of less pain, without the orthopedic damage associated with chronic bleeding. As a result, most children born with hemophilia in the U.S. today can look forward to long, healthy and active lives.